Erythrodermic flare‐up of psoriasis with COVID‐19 infection: A report of two cases and a comprehensive review of literature focusing on the mutual effect of psoriasis and COVID‐19 on each other along with the special challenges of the pandemic

Abstract The COVID‐19 pandemic has been extra challenging for patients with chronic diseases. Psoriasis is one of the chronic conditions that its treatment mostly relies on immunosuppressants. In this study, we report two cases with a long history of psoriasis that COVID‐19 infection caused them to undergo erythrodermic psoriasis.


| INTRODUCTION
Since the emergence of the novel COVID-19 virus, chronic health conditions have been vastly impacted either directly through the infection and the immune responses followed by it or indirectly by imposing fear on some patients and causing them to restrict or delay their routine follow-up cares, which might aggravate their condition. 1,2 Erythrodermic psoriasis is a severe and scarce form of psoriasis vulgaris that affects the entire body and provokes systemic inflammation with unknown certain etiology in which interleukin-4, interleukin-13, and TNF alpha have been suggested to have prominent roles. 3 Here, we present two cases of psoriatic patients that developed symptoms of erythrodermic psoriasis after affliction with COVID-19.

| Case 1
A 50-year-old male with a 20-year history of psoriasis vulgaris was presented with erythrodermic psoriasis to the emergency department of our hospital. He was a retired employee, and his BMI was 28.68, had no other underlying health condition, and had been a cigarette smoker for 21 years (42 pack-years) but had quit smoking 8 years ago and mentioned occasional consumption of alcohol. One month prior to the admission, he had been in close contact with a COVID-19-positive patient and developed fever and chills, fatigue, and myalgia shortly after. Real-time PCR test was not carried out on, but in the chest CT scan, the typical signs of COVID-19 infection were evident.
He had quarantined himself at home for 2 weeks and began taking Naproxen 250 mg tablet (three times a day), Hydroxychloroquine 500 mg tablet (twice a day), and Nacetyl cysteine effervescent (daily) for 5 days and then without consulting a doctor added Amoxicillin 500 mg (three times a day) and Azithromycin 250 mg (daily) to his regimen. He had also delayed receiving Adalimumab due to his COVID-19 infection. The patient stated that 2 days after taking the antibiotics, he developed general erythema and pruritus scaling that started from his palms and the soles of his feet with severe paresthesia. The physical examination revealed fever, weakness, and facial SUMMARY • Continuation of immunosuppressive treatments in patients that become infected with COVID-19 is a matter of controversy. • COVID-19 causes cytokine storm in the body that might aggravate diseases with an inflammation-based pathophysiology. • Current information is still limited and controversial about the dynamic association between COVID-19 and pre-existing immune-mediated diseases (including psoriasis) in terms of the impact of COVID-19 infection and its treatments on the course of the underlying disease and the effect of the pre-existing disease and its treatments on the COVID-19 infection. Although a number of studies and recommendations about this concern exist but since there is still no general agreement, further investigation is crucial. • When a patient with a pre-existing immune-mediated disease is infected with COVID-19, cessation or alteration of the routine medications, the cytokine storm caused by the infection or the effects of COVID-19 medications might change the course of the underlying disease and flare-ups might occur. What this study adds? • Patients who had discontinued their psoriasis medications prior or after being afflicted with COVID-19 were more likely to experience severe psoriasis flare-ups. • Patients who had not missed their scheduled biologic administration were likely to experience mild COVID-19 symptoms while their psoriasis condition remained unchanged. • Biologics might potentially help with COVID-19 infection recovery.
• Morbidity and mortality in psoriatic patients were not higher than the general population. • Evidence suggests that biologics are safe in the course of COVID-19 infection and patients who had stopped their scheduled injection were more likely to experience flare-up, therefore, withholding biologics due to COVID-19 infection is not advisable. • Although the use of non-biologics in the pandemic era is more controversial but some studies suggest that like biologics, non-biologics can also have desirable effects on overcoming the hyperinflammation state caused by COVID-19. • There are substantial controversies about starting non-biologics in patients at the time of being infected with COVID-19 but a lot of studies suggest continuing non-biologics in patients who were receiving them before being infected with COVID-19. • Using Glucocorticoids is one of the main therapeutic strategies in patients with severe COVID-19 symptoms; in psoriatic patients, administration of glucocorticoids during the course of COVID-19 infection might affect the patient's psoriasis presentation, as in some cases early after the administration of steroids, psoriatic lesions seem to be mitigated and after finishing the course of treatment, some patients have reported to experience certain degrees of psoriasis flare-up.
edematous accompanied by generalized skin redness and desquamation. (Figures 1 and 2) No signs of tachycardia, mucosal involvement, or swollen ankles were detected, and the rest of his examination was unremarkable. He had been a known case of psoriasis for about 20 years, he had been receiving Infliximab until 4 years ago, and his condition had been under control but after Infliximab was no longer covered by insurance, his medication was switched to Adalimumab, which relatively controlled his condition with occasional mild flare-ups. The patient started receiving Methotrexate 10 years ago, but 6 months ago, it was discontinued due to hepatic cirrhosis. Due to his COVID-19 infection, he had skipped one session of his Adalimumab therapy, which might have been a reason to this sudden flare-up. Laboratory evaluation was significant for high lactic acid dehydrogenase (LDH = 549, normal range 140-280 U/L), and the rest of his laboratory results were within normal range Table 1. Based on his clinical evaluation, the clinical diagnosis of severe erythrodermic psoriasis was made for him. After  initial managements of his condition, he was treated with Cyclosporine 10 mg tablet (three times a day), Prednisone 50 mg tablet (daily), Neostigmine 25 mg capsule (twice a day), Acyclovir 80 mg tablet (three times a day), topical ointment of Mometasone (twice a day), and a mixed lotion of Eucerin and fluticasone (twice a day) on his lesions. He was discharged in a good condition and symptom free. Up to the time of this report, he has not experienced any psoriasis flare-ups or hospitalization.

| Case 2
A 57-year-old female with a history of diabetes, hepatic cirrhosis, and psoriasis (for 15 years) was admitted to the internal medicine ward of our hospital with generalized edema and ascites along with general erythrodermic psoriasis legions on her trunk, face, upper, and lower limbs (Figure 3). She was isolated from other patients because despite her nontypical symptoms, she was suspected to be infected with COVID-19. We visited the patient for dermatology consultation. She was a housewife, and her BMI was 27.18. For diabetes, she had been receiving insulin, and for psoriasis, she had been receiving MTX for more than 10 years until being diagnosed with hepatic cirrhosis a few months ago. She had not been receiving any other substitutes for psoriasis ever since. She mentioned no history of smoking or alcohol consumption. The infectious disease department consulted us to refrain from administering Adalimumab or any other immunosuppressant. Therefore, we tried to manage her legions with topical agents (including Betamethasone and Vaseline ointment and Clobetasol lotion). A PCR test was obtained from her and confirmed her COVID-19 infection, and she started receiving the routine COVID-19 treatment according to national guidelines at the time. Unfortunately, her COVID-19 condition was rapidly deteriorated and she was admitted to the intensive

| METHOD
We searched Medline database using the following keyboards: "corona virus," "COVID-19," "SARS-Cov-2," "psoriasis," "erythrodermic psoriasis," and "psoriasis arthritis" and chose 13 relevant case reports and 6 relevant original articles. not only have reported successful recovery in biologic receiving patients but also suggest that biologics could be considered as potential life savers against COVID-19 induced cytokine storm. 9,10 Another type of immunosuppressants that are regularly prescribed for psoriasis is nonbiologics, which include methotrexate (MTX) and cyclosporine. 11,12 Existing studies advice against the use of these agents for it, which has been demonstrated that MTX is accompanied with up to 45% increased risk of COVID-19 infection. On the contrary, some studies find the anti-inflammatory effects of MTX desirable in the inflammatory phase of COVID-19 infection. 13,14 A case report has looked into 4 cases that were in close contact and 3 out of 4 of them were infected with COVID-19 but the fourth one that was under treatment with MTX because of psoriasis did not become infected. 15 Although cyclosporine has been reported to be safer than MTX in the course of COVID-19 infection but still a number of studies suggest abstain from it. 16 Another challenging aspect of this matter is that COVID-19 infection itself provokes immune responses that can be progressed to cytokine storm resulting in a hyperinflammation state in the body that attributes to the pathogenesis of psoriasis, which similarly causes hyperinflammation. 17 This immense cytokine release might exacerbate psoriatic patients' condition as it has been reported by different studies. 18,19 We have discussed in our previous studies about the potential association between COVID-19 and dermatology conditions. 6,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Using glucocorticoids is one of the main therapeutic strategies in patients with severe COVID-19 symptoms; in psoriatic patients, the administration of glucocorticoids during the course of COVID-19 infection might affect the patient's psoriasis presentation, as in some cases early after the administration of steroids, psoriatic lesions seem to be mitigated, and after finishing the course of treatment, some patients have reported to experience certain degrees of psoriasis flare-up. 6,[19][20][21][22][25][26][27][28][29][30][31] Currently, there is no general consensus about the medications used in COVID-19 treatment but from the beginning of the pandemic Hydroxychloroquine (HCQ) has been one of the most common choices in COVID-19 treatment. 34 Certain case reports have suggested HCQ to have worsening effects on the course of psoriasis. Although the exact cause of this effect is not entirely clear, some studies attribute this to an elevation of IL-17 in patients taking HCQ. 35 Sachdeva et al. have reported 9 cases with a new onset of psoriasis after taking HCQ. 36 Although they hold HCQ responsible for this, a handful of case reports exist on the topic of new psoriasis onsets after COVID-19 infection, which conclude these new onsets to be the result of the infection itself. 35 Lehmann et al. have even reported a case with a new onset of psoriasis after COVID-19 vaccination. 37 Another commonly used medication in COVID-19 is azithromycin. Although the benefits of this macrolide in COVID-19 treatment have remained controversial, it is considered to have a potential immunomodulatory effect on keratocytes and epidermal Langer Hans cells, which could be helpful in the improvement of psoriatic legions. 38 But data on this matter are very limited and further investigation is crucial.

| DISCUSSION
As it was mentioned, our first case had consumed amoxicillin as well. Although there is existing evidence about the association between consumption of some antibiotics like tetracycline and psoriasis aggravation, flareups following derivatives of penicillin administration have been reported to be extremely rare. Therefore, we assume that amoxicillin may not have been very likely to be the culprit that caused the exacerbation. 39 Both of our cases had stopped their immune suppressants before being infected with COVID-19, and they both had consumed HCQ. Although the main cause of their flare-up is not entirely clear but according to previous studies, we can assume that stopping their immunosuppressive therapies without consulting their doctors might have made them more susceptible to the COVID-19related cytokine storm; moreover, the use of HCQ might have aggravated their underlying psoriasis.
With the combination of limited access to their medications due to the COVID-19 outbreak, inflammation caused by COVID-19 infection and the adverse effects of the medications currently in use for opposing COVID-19 infection, adding to it the stress that the COVID-19 causes (which is considered another factor in psoriasis aggravation), chronic disease patients, and their doctors are faced with a dilemma for finding a sweet spot of managing their patients' underlying psoriasis condition and overcoming the infection caused by COVID-19. 40 Overall, evidence suggests that discontinuing the immunosuppressive therapies in patients who had been using them before being infected with COVID-19 is not advisable, while more evidence points to biologics being safe but even nonbiologics that are controversial for their safety are recommended to be continued with caution.
To have a better understanding of the clinical aspects and managements of psoriasis in the COVID-19 pandemic, we have reviewed and summarized reported cases of psoriasis patients diagnosed with COVID-19 and cases with new onset of psoriasis in COVID-19 cases. We categorized case reports into three main groups.

| COVID-19 infection in known psoriasis patients without specific changes in psoriatic symptoms
A number of studies have reported an asymptomatic course of COVID-19 infection in psoriatic patients that were on biologic treatment without any changes in their psoriasis condition. Balestri 44,45 The aforesaid cases were all receiving biologics, and no alteration in the course of their psoriasis was reported. Nasiri et al. reported a patient under treatment with MTX and cyclosporine with uncontrolled psoriasis and intermittent severe flare-ups that also recovered without being hospitalized. 46 However, his psoriatic legions were worsened at first because he had discontinued his immunosuppressive medications, but then his legions gradually improved.

| COVID-19 infection in known psoriasis patients with specific changes in psoriatic symptoms
Gananandan et al. reported a 38-year-old male with chronic active psoriatic plaques that 6 days after the onset of fever caused by COVID-19 developed multiple erythematous legions on his lower limbs. 47 In Ghalamkarpour's paper, a 45-year-old male with a 20-year history of psoriasis had erythrodermic flare-up following COVID-19 infection. Moreover, the patient had discontinued his psoriasis medications before being infected with COVID-19. 48

COVID-19 patients
De Stefano et al. reported a male in his thirties without any previous history of psoriasis that was infected with COVID-19 with mild symptoms, but 10 days after recovery from COVID-19, psoriatic legions started appearing from his groin and the extensor surface of his elbows. 49 Another similar case was a 62-year-old female reported by Mathieu et al. that developed psoriatic legions 2 weeks after COVID-19 recovery. 50 Another remarkable case was reported Lehmann et al. describing a new onset of guttate psoriasis after COVID vaccination. 37

| CONCLUSION
Although the main reason for their flare-up in not entirely clear in the two cases that we reported but we assume that discontinuation of psoriasis systemic treatment and not receiving any immunosuppressant had made them more susceptible to the COVID-19-related cytokine storm and disease flare-up. Our literature review revealed that COVID-19 in psoriatic patients is not accompanied with any further morbidity and mortality compared to the general population. Patients that had discontinued their psoriasis medications were more likely to experience psoriasis flare-ups, but patients that maintained their routine medications were less likely to experience any alterations in their underlying psoriasis. A considerable number of studies suggest that biologics seemed to have helped psoriatic patients mitigate their COVID-19 symptoms and accelerated their recovery from COVID-19. Some studies suggest that taking HCQ might aggravate the underlying psoriasis condition.
Most flare-up cases were in patients that were not receiving biologics and had discontinued their nonbiologic immunosuppressive medications, whether this has been due to the COVID-19-related cytokine storm or the medications given to them for COVID-19 is not clear but when the underlying psoriasis is neglected, COVID-19 is more likely to trigger flare-up.